1. Field of the Invention
The present invention relates to supramolecular assemblies as delivery vehicles for detecting, imaging, and treating target tissues, such as cancerous or precancerous tissue.
2. Description of Related Art
A number of proteases are associated with disease progression in cancer, and are known to be over-expressed by various cancer cell lines, as shown in FIG. 1. Examples include Matrix Metalloproteinases (MMPs), Tissue Serine Proteases, and the Cathepsins. Many of these proteases are either upregulated in the cancer cells (i.e., have a much higher activity in the tumor than in healthy tissue), mis-expressed (i.e., are found in compartments where they should not be found), or are involved in embryonic development (but should not be found to any significant extent in an adult cell). As shown in FIG. 1, the stages of disease progression are separated into four events: initial mutation, cell survival/tumor progression, angiogenesis (development of new blood vessels), and invasion/tissue remodeling. The array of proteases associated with each stage can give a good picture of how far the cancer has progressed and what the prognosis will be.
There are 21 different known MMPs that are grouped into families based on their substrates: collagenases, gelatinases, stromelysins, matrilysin, metalloelastase, enamelysin, and membrane-type MMPs. MMPs are usually produced by stromal cells surrounding a tumor, and although not produced by the cancerous cells themselves, are vital to cancer survival and progression for several reasons. First, they cleave cell surface bound growth factors from the stromal and epithelial cells and release them to interact with the cancer cells to stimulate growth. Second, they play a role in angiogenesis by opening the extracellular matrix (ECM) to new vessel development as well as by releasing pro-angiogenic factors and starting pro-angiogenic protease cascades. MMPs play a major role in tumor metastasis by degrading the ECM and the basement membrane (BM), allowing the cancer cells to pass through tissue barriers, leading to cell invasion. They also release ECM and BM fragments, which stimulates cell movement.
Several serine proteases have well-documented roles in cancer as well, especially urokinase plasminogen activator (uPA) and plasmin Elevated expression levels ofurokinase and several other components of the plasminogen activation system have been found to be correlated with tumor malignancy. uPA is a very specific protease that binds to its receptor, uPAR, and cleaves the inactive plasminogen (a zymogen) to the active plasmin. This is the first step in a well-known cascade that causes angiogenesis in tumors. It is believed that the tissue degradation that follows plasminogen activation facilitates tissue invasion and contributes to metastasis. Plasmin is a somewhat non-specific protease that goes on to cleave proteins or peptides including activating procollagenases, degrading the ECM, and releasing/activating growth factors. Although plasmin is somewhat non-specific and a consensus sequence is hard to determine, uPA does have a well-defined consensus sequence (SEQ ID NO: 1).
Cathepsins, with a few exceptions, are cysteine proteases. Often found in the lysosomal/endosomal pathway, cathepsins usually operate at low pH values, but some are still active at neutral pH. Three of the cathepsins, B, D, and L, are active at neutral pH and are often misexpressed in cancer, causing activation outside of the cells. This activation outside of the cell can cause ECM degradation.
A major reason cancer therapy fails is that the undesired side effects of most cancer drugs limit the amount of the drug that can be delivered systemically and thus the amount of drug that is ultimately delivered to the tumor. A more specific method of delivery would decrease systemic delivery (and thus unwanted side effects) and increase tumor delivery (increasing effectiveness of the drug). Such a therapy would be much less likely to fail because of low dosages or be stopped by the patient due to overwhelming side effects. In addition, despite recent advances, there remains a need for improved detection and imaging of cancerous tissues.